The use of gallium administered in a variety of gallium-containing compounds to treat mammalian and human disease is well known. Gallium was initially identified as an antineoplastic agent by Hart, et al. (Proc Natl Acad Sci USA, Vol. 68, 1971, pp. 1623–1626), and has subsequently been reported to be effective against a variety of cancers, including particularly hematological malignancies such as leukemias, lymphomas (e.g., non-Hodgkin's lymphoma), multiple myeloma and Hodgkin's Disease. See, e.g., D. J. Straus, Semin Oncol Vol. 30(2 Suppl 5), April 2003, pp. 25–33; E. A. Van Leeuwen-Stok, et al., Leuk Lymphoma, Vol. 31(5–6), November 1998, pp. 533–544; R. P. Warrell, et al., Cancer Treat Rep, Vol. 71, 1987, pp. 47–51; M. S. Myette, et al., Cancer Lett, Vol. 129(2), Jul. 17, 1998, pp. 199–204; C. R. Chitambar, et al., Am J Clin Oncol, Vol. 20(2), April 1997, pp. 173–178.
It has also been reported that gallium is a potent inhibitor of bone resorption, leading to its use to treat hypercalcemia associated with cancer (R. P. Warrell, et al., J Clin Invest, Vol. 73, May 1984, pp. 1487–1490) as well as other diseases characterized by accelerated bone loss, such as multiple myeloma (R. P. Warrell, et al., J Bone Mineral Res, Vol. 5 (Suppl 2), Aug. 28, 1990, pp. S106; R. P. Warrell, et al., J Clin Oncol, Vol. 11(12), December 1993, pp. 2443–2450), bone metastases (R. P. Warrell, Cancer, Vol. 80, 1997, pp. 1680–1685), hyperparathyroidism (U.S. Pat. No. 4,529,593; C. R. Chitambar, Semin Oncol, Vol. 30(2 Suppl 5), April 2003, pp. 1–4), Paget's disease (R. P. Warrell, et al., Ann Int Med, Vol. 113, 1990, pp. 847–851) and osteoporosis (U.S. Pat. No. 4,529,593; R. Bockman, Semin Oncol Vol. 30(2 Suppl 5), April 2003, pp. 5–12). The actions of gallium on bone are different from bisphosphonates, and appear to be mediated by inhibition of the ATPase-dependent proton pump of osteoclasts, which decreases acid secretion (R. Bockman, Semin Oncol Vol. 30(2 Suppl 5), April 2003, pp. 5–12).
Gallium is reported to accumulate at sites of inflammation and infection and has well-known immunosuppressive properties. Macrophages in particular accumulate gallium, presumably as a result of their ability to engulf protein-iron complexes, resulting in inhibition of the release of inflammatory mediators from the cells. See N. Makkonen, et al. Inflamm Res, Vol. 44(12), December 1995, pp. 523–528. Gallium has reported efficacy in animal models of autoimmune disease and hypersensitivity, including type 1 diabetes, experimental autoimmune encephalomyelitis, experimental pulmonary inflammation, cardiac allograft rejection, experimental autoimmune uveitis, endotoxic shock, and systemic lupus erythematosus (G. Apseloff, Am J Ther, Vol. 6(6), November 1999, pp. 327–339). Gallium, therefore, holds particular promise as a therapy for disorders involving the immune system, in particular autoimmune diseases and conditions or diseases involving a cell-mediated (e.g., macrophage-mediated) immune response.
As evidenced by the foregoing, the therapeutic utility of gallium as a component of a variety of compounds and complexes is established. The compounds of the present invention, therefore, will exhibit a similar range of therapeutic activities and utilities as described above. However, gallium compounds that are better tolerated and have better bioavailability are needed.
The use of gallium 3-hydroxy-4-pyrones (maltols), preferably administered orally, to treat gallium-susceptible conditions has been the subject of several United States. Patents, including U.S. Pat. Nos. 5,258,376; 5,574,027; 5,747,482; 5,883,088; 5,968,922; 5,981,518; 5,998,397; 6,004,951; 6,048,851; and 6,087,354 (to Bernstein). The gallium maltol complex is prepared by reacting a gallium salt, such as halide or nitrate, with a 3-hydroxy-4-pyrones in solution. The electrostatic neutral state of the 3:1 gallium maltol complex is reported by Bernstein to improve the bioavailability of the gallium when compared to the ionic gallium salts, such as gallium nitrate.
Gallium triacetate has been reported. However, to the best of our knowledge, use of such gallium compounds as pharmaceutical formulations has not been reported. To the best of our knowledge, other gallium alkyl carboxylate products, including gallium tripalmitate, have not been reported in the literature.
With respect to synthetic routes to prepare gallium tricarboxylates, it has been reported that no appreciable dissolution of the metallic gallium was observed upon refluxing gallium metal in either glacial acetic acid or propionic acid for up to ten days, and the desired gallium tricarboxylates were not produced. Reacting gallium oxide and acetic acid resulted in a low yield of an impure gallium triacetate. A preferred preparative route for gallium triacetate was reported to be an exchange reaction between thallium acetate and gallium trichloride. See I. M. Viktorova, Doklady Akademii Nauk SSSR, Vol. 189, No. 3, November 1969, pp. 541–42 (English translation).
A preparative route for the gallium-containing product, gallium trilactate, is disclosed by Dudley, et al. The synthetic process starts by reacting metallic gallium with hydrochloric and nitric acid, followed by precipitation of gallium hydroxide upon addition of ammonium hydroxide. The gallium hydroxide is, in turn, reacted with lactic acid to produce the trilactate gallium complex. See H. C. Dudley, R. G. Garzoli, J Am. Chem. Soc., Vol. 70, (1948), p. 3942.
Thus, while the pharmaceutical use of the nitrate and maltol salts of gallium to treat numerous diseases and conditions has been reported, the literature does not appear to have identified a pharmaceutical compound composed of gallium tricarboxylate products with a carboxylate substituent of more than three carbons. Indeed, direct, high yield preparative routes starting with either metallic gallium or gallium salts, for even the smaller tricarboxylate complexes, have not been heretofore disclosed. What is needed, therefore, is a high yield preparative route for gallium tricarboxylates of four carbons and higher, for example, for subsequent use as pharmaceutical compounds.